Tumor necrosis factor (TNF) is produced as transmembrane and soluble molecules (Wallach et al., Ann Rev Immunol 1999; 17:331-67; Wajant et al., Cell Death Differ 2003; 10:45-65). Transmembrane TNF (tmTNF) is expressed on the cell membrane as functional homotrimers composed of 26 kDa type-II protomers. Soluble TNF (sTNF) is also a homotrimer, but constituted of 17 kDa tmTNF-protomer-extracellular-domain residue produced by TNF-alpha-converting enzyme (TACE, ADAM-17) shedding. TNF is mainly produced by activated macrophages. TNF mediates a number of vital functions, including structural and functional organization of secondary lymphoid organs, apoptosis and antitumor activity, inhibition of viral replication, immunoregulation and inflammation. TNF also plays important roles in pathogenesis of autoimmune diseases, acute phase reaction, septic shock, fever and cachexia. These diverse functions are induced via cognate interactions between the two TNF forms and two transmembrane receptors, TNF receptor type-1 (TNFR1, TNFRSF1A, p55/60, CD120a) and TNF receptor type-2 (TNFR2, TNFRSF1B, p75/80, CD120b). The receptors have structurally distinct intracellular domains and activate different signaling pathways. It is suggested that TNFR1 and TNFR2 are preferentially activated by sTNF and tmTNF, respectively (Wallach et al., Ann Rev Immunol 1999; 17:331-67; Wajant et al., Cell Death Differ 2003; 10:45-65).
Millions of people die from cancer every year worldwide; cancer is the second leading cause of mortality in the United States. The American Cancer Society reports that, in the United States alone, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. As deaths from cancer generally are increasing, it has been predicted that cancer will become the leading cause of death.
Cancer is an abnormal state in which uncontrolled proliferation of one or more cell populations interferes with normal biological functioning. The proliferative changes are usually accompanied by changes in cellular properties, including reversion to a less differentiated state and an increase in proliferative capacity. The in vitro correlate of cancer is called cellular transformation. Transformed cells generally display several or all of the following properties: spherical morphology, expression of fetal antigens, growth-factor independence, lack of contact inhibition, anchorage-independence, and growth to high density. A need remains for methods for the treatment and prevention of cancer.